Over the past several decades the rate of new drug approvals has declined, in part due to the discovery of fewer first-in-class drugs and to the occurrence of costly late-stage failures.
One root cause of these difficulties is a reliance on disease models that do not accurately predict safety and efficacy in humans and do not reflect the inherent genetic diversity of patient populations.
The 2007 discovery of human induced pluripotent stem cells (iPSCs) offers a platform to solve these problems3,4. In the next five years, iPSCs will prove an essential tool for improving the success of drug discovery and development and will also accelerate the development of cell therapies. iPSC-derived cell models will help reverse the decline in R&D productivity and will prove to be a more cost-effective and efficient means of drug development.
iPSC-derived cells will improve discovery The predominant approach to drug discovery has involved the identification of candidate molecules using simplified and easily controlled target-based screens. While these screens have certainly produced effective medicines, a recent analysis has shown that phenotypic screens, as opposed to targetbased screens, have led to the discovery of more first-in-class drugs5. iPSC-derived cells offer an ideal starting point for phenotypic screening. Exciting results using these models have recently been reported. For example, iPierian used iPSC-derived neurons from Alzheimer’s patients to identify novel secreted forms of tau6. Antibodies to these forms of tau are in preclinical development at Bristol- Meyers Squibb following a $725 million acquisition of iPierian7. iPSC-derived cardiomyocytes have been used to identify new targets for cardiac disease8,9, a therapeutic area that has long been in need of new targets10. Lastly, a GSK-sponsored study of iPSC-derived motor neurons from patients suffering from amyotrophic lateral sclerosis (ALS) led to the identification of a drug candidate for this devastating disease11.
Proof of the value of iPSC models will come from the progress of these therapies in human trials. What is most promising, however, is that these iPSC-derived models allow drug hunters to access the complex systems of a cell as a whole, rather than one particular target or pathway. They also allow for inexpensive and fast in vitro hypothesis testing on fully-functioning cells before initiating expensive clinical trials.
iPSC-derived cells will improve safety testing
In addition to providing better models of disease biology, improved in vitro models of drug toxicity using iPSC-derived cells will help avoid costly late-stage development failures. The potential value of models of drug toxicity can be seen from the failure of the drug candidate BMS-986094. Acquired for $2.5 billion for its promise in treating hepatitis C, a clinical trial was abandoned in 2012 following patient hospitalisations and one patient death due to toxic cardiomyopathy12. Better models of druginduced cardiotoxicity could have prevented this failure.
Several companies have used iPSCderived cardiomyocytes to develop cardiotoxicity assays, demonstrating expected pharmacological properties and better prediction of compound-induced arrhythmias as compared to cell lines expressing the hERG channel protein13,14. These efforts are largely driven by the Comprehensive In Vitro Proarrhythmia Assay (CIPA) collaboration, supported by global partners, which aims to substitute in vitro models for preclinical animal cardiotoxicity studies. In the near future, iPSC-derived cardiomyocytes are likely to eliminate proarrhythmogenic compounds before human trials begin, saving billions of dollars in development costs.
iPSC-derived cells will enable in vitro clinical trials
Before the development of iPSC technology, the only practical way to assess the effect of genetic diversity on drug efficacy and safety was through testing in human volunteers that would often reveal unfortunate toxic side-effects and fail to demonstrate efficacy. iPSCs allow for execution of ‘in vitro clinical trials’ where donor iPSCs are used to make the desired terminal cell type, and to screen for either toxicity or efficacy in vitro in those cells.
The previous example of GSK and its search for ALS therapies provides an example of an in vitro clinical trial for efficacy and genetic diversity, where the intention is to correlate in vivo drug response of the actual patient enrolled in the clinical trial with the in vitro response of the patient’s iPSC-derived cells11. This will provide a measure of the predictive utility of iPSC-based models. In another example, iPSC-derived neuronal cells reflecting familial or sporadic genetic variants linked to Alzheimer’s disease have been used to identify small molecules that inhibit - amyloid toxicity15. In both of these models, genetic variation is built in from the beginning of drug discovery, instead of appearing in the late stages of clinical trials. In an example of how iPSCs might enable development of personalised therapies, patient-derived iPSCs from a patient with mutations in the low-density lipoprotein receptor gene linked to familial hypercholesterolemia have been shown to recapitulate aspects of disease phenotype and drug response16. These are just a few of the ways iPSC-derived lines can be used to develop therapies for diseases associated with specific genetic differences in realworld populations.
iPSC-derived cells will improve cell therapy
Despite profound improvements in medical care over the past century, most treatments do not reverse the fundamental underlying disease pathology. Nowhere is this more apparent than in diseases such as agerelated macular degeneration, Parkinson’s disease and heart failure, in which the loss of functional cells are a primary cause. Current therapies do not address cell loss and may at best slow the inexorable decline into infirmity. The ability to manufacture specific types of cells to tight specifications in virtually unlimited quantities paves the way for a new era in medicine where patient cells are replaced or regenerated. These cells can either be derived from the patient’s own iPSCs or sourced from genetically similar individuals.
In the US, a trial by the National Eye Institute using patient-derived cells to treat dry AMD will soon begin17. As cell-based therapies begin to demonstrate efficacy, people will increasingly bank cells for personal use. Cell banks will expand into an entirely new industry, following the path of umbilical cord blood banking.
In a complementary approach to autologous cell therapies, iPSCs available from HLA ‘superdonor’ genetic backgrounds can be used in regenerative medicine applications18. In the near future, banks of prescreened iPSC lines with known HLA specificities will reduce the possibility of immune rejection, speed up identification of a matched donor and allow for large quantities of cell production in these applications.
iPSC-derived cells will lead to dramatic improvements in the treatment of orphan diseases
Orphan diseases are by definition rare but are actually common in aggregate. As we understand disease better, we are coming to realise that all diseases may be ‘orphan diseases’ in the sense that individual genetic makeup is variable and makes each of us unique. iPSC-based phenotypic screening offers a more efficient way to develop therapies for orphan diseases. Combined with drug repurposing libraries, iPSC-based screens could lead to a renaissance in orphan disease drug discovery by making the process economically feasible for smaller, defined, patient populations.
By virtue of their fundamental properties of immortality and pluripotency, iPSCs enable the controlled manufacture of essentially limitless quantities of virtually any human cell type. Because iPSCs can be made from any donor, it is now possible to faithfully represent genetic diversity, including individual genotypes, for research and cell therapy. While these distinct attributes can enhance research productivity in different ways, when applied in combination, they are revolutionary. Now that we are able to routinely produce iPSCderived cells at the scale and purity required for drug development and cell therapy, the next five years will be characterised by improved pharmaceutical productivity and new cell therapies.
1 Scannell, JW, Blanckley, A, Boldone, H, Warrington, B (2012). Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov 11:191-200.
2 Pammoli, F, Magazzini, L and Riccaboni M (2011). The productivity crisis in pharmaceutical R&D. Nat Rev Drug Discov 10(6):428-438.
3 Takahashi, K, Tanabe, K, Ohnuki, M, Ichisaka, T, Tomoda, K, and Yamanaka, S (2007). Induction of human pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861-872.
4 Yu, J, Vodyanik, MA, Smuga-Otto, K, Antosiewicz- Bourget, J, Frane, JL, Tian, S, Nie, J, Jonsdottir, GA, Ruotti, V, Stewart, R, Slukvin, II and Thomson, JA (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917-1920.
5 Swinney, DC and Anthony, J (2011). How were new medicines discovered? Nat Rev Drug Discov 10(7):507-519.
6 Bight, J, Hussain, S, Dang, V, Wright, S, Cooper, B, Byun, T, Ramos, C, Singh, A, parry, G, Stagliano, N and Griswold-Prenner, I (2015). Human secreted tau increases amyloid-beta production. Neurobiol Aging 36:693-709.
7 http://www.fiercebiotech.com/story/bristol-myers-targetsneurodegenerative- diseases-725m-deal-buy-ipierian/2014- 04-29.
8 Wu, H, Lee, J, Vincent, LG, Wang, Q, Gu, M, Lan, F, Churko, JM, Sallam, KI, Matsa, E, Sharma, A, Gold, JD, Engler, AJ, Xiang, YK, Bers, DM and Wu, JC (2015). Epigenetic regulation of phosphodiesterases 2A and 3A underlies compromised -adrenergic signaling in an iPSC model of dilated cardiomyopathy. Cell Stem Cell 17(1):89-100.
9 Aggarwal, P, Turner, A, Matter, A, Kattman, SJ, Stoddard, A, Lorier, R, Swanson, BJ, Arnett, DK and Broeckel, U (2014). RNA expression profiling of human iPSC-derived cardiomyocytes in a cardiac hypertrophy model. PLoS ONE 9(9): e108051. doi:10.1371/journal.pone.0108051.
10 Kaye, DM and Krum, H (2007). Drug discovery for heart failure: a new era or the end of the pipeline? Nat Rev Drug Discov 6(2):127-139.
11 McNeish, J, Gardner, JP, Wainger, BJ, Woolf, CJ and Eggan, K (2015). From dish to bedside: lessons learned while translating findings from a stem cell model of disease to a clinical trial. Cell Stem Cell 17(1):8-10.
12 Ahmad, T, Yin, P, Saffitz, J, Pockros, PJ, Lalezari, J, Siffman, M, Freilich, B, Zamparo, J, Brown, K, Dimitrova, D, Kumar, M, Manion, D, Heath-Chiozzi, M, Wolf, R, Hughes, E, Muir, AJ and Hernandez, AF (2015). Cardiac dysfunction associated with a nucleotide polymerase inhibitor for treatment of hepatitis C. Hepatol 62(2):409-416.
13 Harris, K, Aylott, M, Cui, Y, Louttit, JB, McMahon, NC and Sridhar, A (2013). Comparison of electrophysiological data from human-induced pluripotent stem cell-derived cardiomyocytes to functional preclinical safety assays. Toxicol Sci 134(2):412-426.
14 Guo, L, Abrams, RMC, Babiarz, JE, Cohen, JD, Kameoka, S, Sanders, MJ, Chiao, E and Kolaja, KL (2011). Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci 123(1):281-289.
15 Freude, K, Pires, C, Hyttel, P and Hall, VJ (2014). Induced pluripotent stem cells derived from Alzheimer’s disease patients: the promise, the hope, and the path ahead. J Clin Med 3(4):1402-1436.
16 Cayo, MA, Cai, J, DeLaForest, A, Noto, FK, nagaoka, M, Clark, BS, Collery, RF, Si-Tayeb, K and Duncan, SA (2012). JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia. Hepatol 56(6):2163-2171.
17 http://www.genengnews.com/gen-news-highlights/cdireceives- 1-2m-nei-contract-to-develop-ipscs-for-amdtrial/ 81250519/?kwrd=induced%20pluripotent%20stem%2 0cells.
18 Turner, M, Leslie, S, Martin, NG, Peschanski, M, Rao, M, Taylor, CJ, Trounson, A, Turner, D, Yamanaka, S and Wilmut, I (2013). Toward the development of a global induced pluripotent stem cell library. Cell Stem Cell 13:382-384. A